Risk Assessment and Management Strategy of Two New Nitrosamine Drug Substance Related Impurities (NDSRIs) in a Pharmaceutical Drug Product for the Treatment of a Rare Disease- from Prediction to Control.

N-nitrosamines are a class of compounds belonging to the "cohort of concern" and characterized by the linkage of a nitroso group (-N=O) to an amine functional group (-NR). Some of these compounds are mutagenic, genotoxic, and potentially carcinogenic agents in humans, which necessitates control at acceptable safe levels. The current work presents a comprehensive risk assessment and mitigation strategy for two complex diastereomeric nitrosamines as New Drug Substance Related Impurities (NDSRIs) for miglustat 65mg capsules. A sequential risk assessment and management strategy was executed, which included predictive chemistry of formation, organic synthesis, and in-silico mutagenic and carcinogenic risk assessments. These activities were followed by the application of a highly sensitive validated analytical method with a Limit of Quantitation of 6.9 ppb for the combined NDSRIs. Confirmatory testing of three drug product batches were performed as per regulatory requirements to verify adherence to a conservative Acceptable Intake Limit of 18 ng/day for the combined NDSRIs.